Bi-specific T-cell engager

Structure of a BiTE. VH: Heavy chain variable regions. VL: Light chain variable regions. Different specificity is marked with different colours and shapes. The arrows point from N- to C-terminus.

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for the use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.[1]

BiTEs are fusion proteins consisting of two single-chain variable fragments (scFvs) of different antibodies, or amino acid sequences from four different genes, on a single peptide chain of about 55 kilodaltons. One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule.[2][3]

Mechanism of action

A BiTE linking a T cell to a tumor cell.

Like other bispecific antibodies, and unlike ordinary monoclonal antibodies, BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell's apoptosis.[2][4]

This action mimics physiological processes observed during T cell attacks against tumor cells.[4]

Examples

Clinical trials

The following BiTEs are in clinical trials as of July 2010:

Further research

Utilizing the same technology, melanoma (with MCSP specific BiTEs) and acute myeloid leukemia (with CD33 specific BiTEs) can be targeted.[8] Research in this area is currently ongoing. Another avenue for novel anti-cancer therapies is re-engineering some of the currently used conventional antibodies like trastuzumab (targeting HER2/neu), cetuximab and panitumumab (both targeting the EGF receptor), using the BiTE approach.[9] BiTEs against CD66e and EphA2 are being developed as well.[10]

References

  1. ↑ "US Trademark registration no. 3,068,856, serial number 78/040,636.". US Patent and Trademark Office.
  2. 1 2 3 Helwick, Caroline (1 June 2008). "Novel BiTE antibody mediates contact between T cells and cancer cells". Oncology NEWS International 17 (6).
  3. ↑ Rüttinger, D.; Zugmaier, G.; Nagorsen, D.; Reinhardt, C.; Baeuerle, P. A. (2008). "BiTE-Antikörper: Durch Bispezifität T-Lymphozyten gegen Tumorzellen richten" [BiTE antibodies: Directing T lymphocytes against tumor cells by bispecifity]. Journal Onkologie (in German) (4).
  4. 1 2 "BiTE Antibody Platform". Micromet Inc.
  5. ↑ Nagorsen, D.; Bargou, R.; Rüttinger, D.; Kufer, P.; Baeuerle, P. A.; Zugmaier, G. (2009). "Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab". Leukemia & Lymphoma 50 (6): 886–891. doi:10.1080/10428190902943077. PMID 19455460.
  6. ↑ Clinical trial number NCT00635596 for "Phase I Study of MT110 in Colorectal Cancer (CRC), Gastrointestinal (GI) and Lung Cancer (MT110-101)" at ClinicalTrials.gov
  7. ↑ Amann, M.; d'Argouges, S.; Lorenczewski, G.; Brischwein, K.; Kischel, R.; Lutterbuese, R.; Mangold, S.; Rau, D.; Volkland, J.; Pflanz, S.; Raum, T.; Münz, M.; Kufer, P.; Schlereth, B.; Baeuerle, P. A.; Friedrich, M. (2009). "Antitumor Activity of an EpCAM/CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release". Journal of Immunotherapy 32 (5): 452–464. doi:10.1097/CJI.0b013e3181a1c097. PMID 19609237.
  8. ↑ Kischel, R; et al. (2008). "Characterization in primates of MCSP- and CD33-specific human BiTE antibodies for treatment of Melanoma and AML" (PDF). Proc Am Assoc Cancer Res 99. Abs 2404.
  9. ↑ Lutterbuese, R; et al. (2008). "Conversion of cetuximab, panitumumab, trastuzumab and omalizumab into T-cell-engaging BiTE antibodies creates novel drug candidates of high potency" (PDF). Proc Am Assoc Cancer Res 99. Abs 2402.
  10. ↑ Baeuerle, PA; Reinhardt, C (2009). "Bispecific T-cell engaging antibodies for cancer therapy.". Cancer Research 69 (12): 4941–4. doi:10.1158/0008-5472.CAN-09-0547. PMID 19509221.

Further reading

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